Prevalence and clinical significance of anticardiolipin antibodies in patients with type 1 autoimmune hepatitis

There are few case reports on the association between autoimmune hepatitis (AIH) and anticardiolipin antibodies (anti-CLAbs) and/or antiphospholipid syndrome (APLS). We studied the anti-CLAbs prevalence in AIH and other hepatic diseases. We also investigated whether anti-CLAbs are co-factor dependent and which is their avidity since co-factor dependency or increased resistance is associated with APLS. Fifty-nine AIH patients, 228 HCV, 50 HBV, 123 with other non-viral and non-autoimmune liver disorders (nV-nALD) and 267 healthy people were investigated for anti-CLAbs and antibodies against beta-2-glycoprotein I (anti-beta2-GPI). Resistance of IgG anti-CLAbs was evaluated using 2 M urea. IgG anti-CLAbs detected in 39% of AIH, 19.7% of HCV (p=0.006), 14% of HBV (p=0.01), 8.1% of nV-nALD (p=0.000) and 1.1% of healthy (p=0.000). IgG anti-CLAbs were associated with the presence of cirrhosis and active AIH while their resistance to urea was high. Anti-beta2-GPI was detected in two AIH patients. We demonstrated a significantly higher prevalence of anti-CLAbs in patients with AIH compared to other diseases and healthy people. Anti-CLAbs were associated with AIH stage but no association was found with APLS clinical manifestations (thrombosis, pregnancy morbidity, thrombocytopenia). However, their avidity was comparable with that of APLS indicating the need for prospective studies in order to address whether anti-CLAbs in AIH may contribute to the progression of liver disease or APLS development.     

Chronic mucocutaneous candidiasis and systemic lupus erythematosus: a new variant of chronic mucocutaneous candidiasis?

Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to Candida infection of skin, nails, and mucous membranes. Autoimmune endocrinopathies are common in CMC patients, but there are no reports of the involvement of systemic autoimmune disorders. We present here the first case of this kind of association in a patient with an autosomal dominant variant of CMC. The individual had had this disorder since childhood and systemic lupus erythematosus with secondary antiphospholipid syndrome, as well as renal, articular and hepatic manifestations without thymoma.     

Autoimmune hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab

Infliximab and adalimumab are anti-tumor necrosis factor (TNF) alpha agents used for treating Crohn's disease. Autoimmune hepatitis (AIH) is a rare complication of treatment with these drugs. We report on a case of AIH in a patient with Crohn's disease treated with infliximab who fully recovered after drug withdrawal. More interestingly, because there were no other treatment options, the patient was then treated with adalimumab without recurrence of the liver disease and with control of the intestinal disease.     

A case of hypopituitarism and primary hypothyroidism associated with antiphospholipid syndrome]

Recent reports have indicated that antiphospholipid antibodies (aPL) are related to other clinical manifestations such as cardiac valve lesions and hemolytic anemia besides the major clinical features of antiphospholipid syndrome (APS), including thrombocytopenia, and recurrent fetal demise. We recently encountered a case of multiple hormonal deficiencies in the pituitary gland and hypothyroidism associated with an APS. Hypopituitarism of the patient had occurred after her delivery and a magnetic resonance imaging (MRI) examination disclosed "empty sella" of the hypophysis, so she was thought to have Sheehan's syndrome. There has been a few reports describing the relationship between aPL and endocrine disorders. aPL-related onset of these diseases may be more frequent than is generally appreciated.     

Catastrophic antiphospholipid syndrome: a rare cause of disseminated microvascular thrombotic injury - a case report with pathological and molecular correlative studies

Catastrophic antiphospholipid syndrome (CAPS) is a severe and rare variant of antiphospholipid syndrome (APS) characterized by acute multiorgan failure due to small vessel thrombi in patients with positive antiphospholipid antibodies. We report a fatal case of catastrophic antiphospholipid syndrome in a young woman with a history of polymyositis and Hodgkin lymphoma. The patient was admitted to hospital because of severe foot pain following several weeks of skin ulcerations. Doppler ultrasonography showed evidence of arterial ischemia of the both lower extremities. Despite anticoagulation, immunosuppression, plasmapheresis and antibiotic therapy, she developed cutaneous gangrene, retroperitoneal hematoma, ileus, and acute respiratory and renal failure that resulted in death. Autopsy showed multifocal vascular injury and microthrombi with associated hemorrhages and infarcts in multiple organs. The patient had normal levels of functional protein C and protein S and a normal level of plasma homocysteine. Tests for common thromophilic gene mutations including prothrombin 20210, factor V Leiden 1691, and methylene tetrahydrofolate reductase 677 were negative. To our knowledge, this is the first CAPS patient with molecular studies for genetic prothrombotic mutations. Our report showed that there was no association between the development of CAPS and inherited thromophilia.     

Elevated serum BAFF levels in patients with autoimmune hepatitis

Serum cytokines are thought to be involved in autoimmune hepatitis (AIH) pathogenesis via immune dysregulation. B-cell activating factor belonging to the tumor necrosis factor family (BAFF) is a member of the tumor necrosis factor (TNF) superfamily and is known for its role in the survival and maturation of B cells. The aim of the study was to evaluate the serum levels of BAFF in patients with AIH and determine its relation to the clinical features of AIH. We examined serum BAFF levels in 55 patients with AIH, 14 patients with acute hepatitis (AH), 33 patients with chronic hepatitis C, and 33 healthy subjects by enzyme-linked immunosorbent assay. Liver function tests, quantitative immunoglobulin, and antinuclear antibody levels were also assayed in AIH patients. Serum BAFF levels were elevated in AIH patients compared with healthy subjects (AIH: 2.07+/-1.21 pg/ml, control: 0.77+/-0.22 pg/ml). Similarly, serum BAFF levels were significantly higher in AIH patients compared with AH or chronic hepatitis C patients. There was a positive correlation between BAFF and aspartate aminotransferase (r=0.513, p<0.0001), alanine aminotransferase (r=0.435, p<0.0001), total bilirubin (r=0.419, p<0.01), and soluble CD30 (r=0.579, p<0.0001) in AIH patients. However, there was no correlation between BAFF and levels of gammaglobulins or titer of antinuclear antibodies. Corticosteroid treatment resulted in marked reduction in serum BAFF levels in AIH patients. These results suggest that BAFF contributes to liver injury and disease development in AIH patients.     

Mania: psychiatric manifestations of the antiphospholipid syndrome

BACKGROUND: Antiphospholipid syndrome (APS) is a prothrombotic condition characterized by recurrent vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies. Central nervous system (CNS) involvement is a prominent feature of APS, and many neurological manifestations have been described in published reports. There are limited data on psychiatric syndromes occurring in association with APS, and there have been no previous reports of mania associated with APS. METHOD: The authors present the case of a 31-year-old man who experienced an acute manic episode in association with APS. They review the literature on psychiatric manifestations of APS, discuss potential mechanisms of CNS pathogenesis, and consider diagnostic and treatment implications of the co-occurrence of APS and psychiatric symptoms.     

Bone density changes in pregnant women treated with heparin: a prospective, longitudinal study.

Heparin plus aspirin significantly improves the live birth rate of women with primary antiphospholipid syndrome. Osteopenia is a major concern of long-term heparin therapy. We studied prospectively the bone mineral density (BMD) changes during pregnancy and the puerperium in 123 women with primary antiphospholipid syndrome treated with low-dose aspirin and subcutaneous low-dose heparin (46 women took unfractionated heparin and 77 took low-molecular-weight heparin). Lumbar spine, neck of femur and forearm BMD were measured, using dual energy X-ray absorptiometry, at 12 weeks gestation, immediately postpartum and 12 weeks postpartum. The mean heparin duration was 27 weeks (range 22-29). During pregnancy, BMD decreased by 3.7% (P < 0.001) at the lumbar spine and by 0.9% (P < 0.05) at the neck of femur with no significant change at the forearm. Lactation was associated with a significant decrease in the lumbar spine and neck of femur BMD. There was no significant difference in BMD changes between the two heparin preparations. No woman suffered a symptomatic fracture. Long-term heparin treatment during pregnancy is associated with a small but significant decrease in BMD at the lumbar spine and neck of femur. This decrease is similar to that previously reported to occur in untreated pregnancies.     

Intravenous immunoglobulin therapy in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune disorder defined by the occurrence of venous and arterial thromboses and pregnancy morbidity, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies. There is both laboratory and clinical evidence for the beneficial role of intravenous immunoglobulin (IVIg) in APS. Data on the use of IVIg in patients with APS have focused on its obstetric complications and antiphospholipid antibodies-positive patients undergoing in vitro fertilization, but there are also case reports about treatments of other clinical manifestations (mainly hematological) of the syndrome. Future research should determine when to use anticoagulation, IVIg, or both in the treatment of APS.     

Abstract 21-30

21. Nodular regenerative hyperplasia of the liver as the presenting manifestation of primary APS. A case report22. Prevalence of antiphospholipid and antinuclear antibodies in patients with active lupus nephritis23. IgM anticardiolipin antibodies and antiphospholipid syndrome24. Antiphospholipid antibodies(APLA)-possible markers in accelerated atherosclerosis25. Qinacrine added to ongoing therapeutic regimens is highly beneficial in active SLE and attenuates anticardiolipin antibody production26. Induction of pathogenic APL by CMV peptides27. Successful pregnancy outcome in a patient with Gaucher's disease and anti-phospholipid syndrome28. Antiphospholipid antibody levels in intravenous immunoglobulin (IVIg) preparations29. Transverse myelitis in patients with antiphospholipid antibodies: The importance of early diagnosis and treatment30. Antiphospholipid syndrome, antiphospholipid antibodies and atherosclerosis     

Aortic valve replacement and perioperative management in hemodialyzed patient wth antiphospholipid syndrome

Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies, hypercoagulability, and prolonged phospholipid-dependent coagulation indices such as activated clotting time (ACT). Perioperative thrombotic complications are frequent among patients with antiphospholipid syndrome submitted to cardiac surgery, therefore, in these patients, heparin-protamine titration for anticoagulation monitoring is particularly recommended. We demonstrate a case of 42-year-old hemodialyzed patient with antiphospholipid syndrome, submitted to the replacement of stenotic aortic valve. In our patient celite ACT and heparin concentration during cardiopulmonary bypass did not correspond to each other. Anticoagulation based on heparin concentration assessment resulted in safe perioperative hemostatic management.     

A case of cerebral infarct in combined antiphospholipid antibody and ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome is a serious complication of ovulation induction and has a diverse clinical spectrum from edema to thromboembolism. Antiphospholipid antibody syndrome, one of the well known hypercoagulable states, can be also manifested as an arterial or venous thrombosis and recurrent spontaneous abortion. Sometimes a patient with antiphospholipid antibodies might not notice a miscarriage and seek for assisted reproduction treatment, which harbors a chance of developing ovarian hyperstimulation syndrome. If this happens, the ovarian hyperstimulation syndrome can exacerbate the thrombotic complication of underlying antiphospholipid antibody syndrome, resulting in a catastrophic vascular event. The authors experienced a case of middle cerebral artery infarct, which developed during ovarian hyperstimulation syndrome in a 33-yr-old woman with a previous history of fetal loss. An elevated titer of anticardiolipin antibodies was noticed and persisted thereafter. The authors suggest screening tests for the presence of antiphospholipid antibodies before controlled ovarian hyperstimulation.     

Autoimmune hepatitis in primary Sjogren's syndrome: pathological study of the livers and labial salivary glands in 17 patients with primary Sjogren's syndrome

Although primary Sjogren's syndrome (pSS) is an autoimmune exocrinopathy, the involvement of liver has been reported. Because no study focusing on autoimmune hepatitis (AIH) in pSS has been published, the purpose of the present study was to perform a clinical and histological examination of the liver, focusing on AIH, in 17 pSS patients. The patients had liver enzyme abnormalities without hepatitis virus infection. In all cases, biopsied livers were examined, and in 10 cases biopsied labial salivary glands were also examined histologically. Based on the authors' diagnostic criteria for AIH in pSS, the liver diseases consisted of AIH (eight cases, 47%), primary biliary cirrhosis (PBC; six cases, 35%), non-specified chronic hepatitis (two cases, 12%) and acute hepatitis (one case, 6%). Lymphoplasmacytic infiltrate, with predominancy of CD3(+) T cells, was noted in both the liver and salivary glands in the patients with AIH. The patients with AIH with severe interface hepatitis had a good response to immunosuppressive therapy. The comparison of liver histology between the PBC with pSS group and the PBC without pSS group showed that the incidence of lymphoid non-suppurative cholangitis was higher in PBC with pSS. In conclusion, the present study offers new information on the relatively common occurrence, diagnostic criteria and treatment effects of AIH in pSS.     

The hepatitic/cholestatic "overlap" syndrome: an Italian experience

BACKGROUND: Patients with hepatitic and cholestatic autoimmune liver disease ("overlap syndrome") represent a diagnostic and therapeutic challenge. AIM: To evaluate the prevalence of the "hepatitic/cholestatic overlap" in a large series of consecutive patients with cholestatic autoimmune liver disease. METHODS: We re-evaluated the diagnosis of 235 patients with autoimmune liver disease, including 70 with type 1 autoimmune hepatitis (AIH), 142 with primary biliary cirrhosis (PBC), and 23 with primary sclerosing cholangitis (PSC), using the revised International Autoimmune Hepatitis Group (IAIHG) scoring system. Anti-mitochondrial, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, perinuclear anti-neutrophil nuclear and anti-soluble liver antigen antibodies were evaluated in each patient. RESULTS: Ten patients (3 with a previous diagnosis of PBC and 7 of PSC) scored as "probable" or "definite" AIH. These patients did not have a specific autoantibody profile. CONCLUSIONS: Among patients with PBC, the occurrence of a PBC/AIH overlapping syndrome is rare (2.1%), whereas among patients with PSC an overlap between PSC and AIH is frequent (30.4%). Whether patients with the hepatitic/cholestatic overlap syndrome would benefit from a combination therapy with immunosuppression and ursodeoxycholic acid remains to be established.     

Retrospective analysis of autoimmune hepatitis-primary biliary cirrhosis overlap syndrome in Korea: characteristics,treatments, and outcomes

Background/Aims

Overlap syndrome of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) (AIH-PBC overlap syndrome) is a rare disease that has not been clearly characterized in Korean patients. This study investigated the clinical features of AIH-PBC overlap syndrome compared with those of AIH and PBC alone.

Methods

This retrospective cohort study included 158 consecutive patients who were diagnosed as AIH (n=61), PBC (n=81), or AIH-PBC overlap syndrome (n=9) based on the Paris and the International Autoimmune Hepatitis Group (IAIHG) criteria from 2001 to 2011 in Korea. We compared the clinical features of these three groups retrospectively, including their biochemical characteristics, treatments, responses, and clinical outcomes.

Results

The AIH-PBC overlap syndrome patients exhibited biochemical characteristics of both AIH and PBC, and showed a similar response to ursodeoxycholic acid (UDCA) monotherapy as for the PBC patients. However, the response of AIH-PBC overlap syndrome patients to UDCA and steroid combination therapy was worse than the response of AIH patients to steroid-based therapy (P=0.024). Liver cirrhosis developed more rapidly in AIH-PBC overlap syndrome patients than in AIH patients group (P=0.013), but there was no difference between AIH-PBC overlap syndrome patients and PBC patients. The rates of developing hepatic decompensation did not differ significantly between the groups.

Conclusions

The AIH-PBC overlap syndrome patients exhibited a worse response to UDCA and steroid combination therapy and a faster cirrhotic progression compared with AIH patients.     

A spectrum of histopathologic findings in autoimmune liver disease

We retrospectively studied 42 liver biopsy specimens from 39 patients who met serologic and histologic criteria of autoimmune liver diseases. We found 10 cases of overlap syndrome (OLS), 10 autoimmune cholangitis (AIC), 10 primary biliary cirrhosis (PBC), and 9 autoimmune hepatitis (AIH) type 1. The following results were obtained: (1) Granulomas and biliary duct lesions were more prominent in PBC and AIC than in OLS and AIH. (2) Bile duct loss was not observed in AIH cases. (3) Features of hepatocellular damage such as piecemeal necrosis, spotty lobular necrosis, and confluent necrosis, were much more prevalent in OLS and AIH than in PBC and AIC. (4) HLA-DR antigen expression by hepatocytes was more frequent in AIH and OLS, whereas the expression of the same antigen by the bile duct epithelium was more frequent in PBC and AIC. We conclude there is a morphologic spectrum in autoimmune liver diseases, in which PBC forms one end of the spectrum, AIH the other, OLS the middle but closer clinically and histologically to AIH than to PBC, and AIC, which seems to be an antimitochondrial antibody-negative subtype of PBC.     

Autoimmune Hepatitis Following Vaccination for SARS-CoV-2 in Korea: Coincidence or Autoimmunity?

Autoimmune hepatitis (AIH) is a chronic, autoimmune disease of the liver that occurs when the body’s immune system attacks liver cells, causing the liver to be inflamed. AIH is one of the manifestations of a coronavirus disease 2019 (COVID-19), as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few cases of AIH have been described after vaccination with two messenger RNA (mRNA)-based vaccines—BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—against SARS-CoV-2. Herein, we report a case of AIH occurring after Pfizer-BioNTech COVID-19 vaccine. A 27-year-old female presented with jaundice and hepatomegaly, appearing 14 days after receiving the second dose of Pfizer-BioNTech vaccine. Her laboratory results showed abnormal liver function with high total immunoglobulin G level. She was diagnosed with AIH with histologic finding and successfully treated with oral prednisolone. We report an AIH case after COVID-19 vaccination in Korea.     

Aspirin desensitization in the treatment of antiphospholipid syndrome during pregnancy in ASA-sensitive patients

PROBLEM: Antiphospholipid syndrome (APS) is associated with thrombosis and poor pregnancy outcome in the presence of antiphospholipid antibodies (aPL). Patients with aPL have a high risk of foetal loss. However, with low-dose aspirin (acetylsalicylic acid; ASA) in combination with subcutaneous heparin, the chances of full-term delivery increase. Nevertheless, ASA treatment is avoided in pregnant, ASA-sensitive women with APS. METHODS: Rapid oral challenge-desensitization to ASA was performed in four pregnant women with a history of APS and aspirin sensitivity. In three patients, desensitization was performed during pregnancy and before the next pregnancy in the fourth. Desensitization was carried out in the ICU using increasing doses of aspirin (0.1-125 mg) over a 24-hr period. RESULTS: Successful ASA desensitization was achieved in all the patients. No severe side effects occurred during the desensitization test. Only one patient required a small oral dose of antihistamines. CONCLUSIONS: Aspirin desensitization may be a safe alternative even during pregnancy if carefully monitored and permit patients with APS to receive treatment with ASA. This would constitute a new indication in pregnant women with APS and ASA sensitivity.     

Co-development of autoimmune hepatitis and Sj?gren's syndrome triggered by the administration of herbal medicines

Autoimmune hepatitis (AIH) has been reported in association with Sjögren''s syndrome (SS). Drug-induced AIH has been rarely reported. A rare case of the co-development of AIH and SS in a 53-year-old woman after the consumption of herbal medicines is described. After admission, the patient complained of dryness in her mouth, and she was subsequently diagnosed with SS, which had not been detected previously. The patient''s bilirubin and aminotransferase levels initially decreased following conservative management; however, they later began to progressively increase. A diagnosis of AIH was made based on the scoring system proposed by the International Autoimmune Hepatitis Group. The patient was administered a combination of prednisolone and azathioprine, and the results of follow-up liver-function tests were found to be within the normal range. This is an unusual case of AIH and SS triggered simultaneously by the administration of herbal medicines.